Examining the Antidepressant Potential of TNF-alpha and Reelin on Associated Behavioural and Neurobiological Markers in a Preclinical Model of Depression

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Depression is a debilitating psychiatric disorder affecting approximately 10% of the world’s population. Cognitive dysfunction is an often ignored aspect of depression, and predicts patient response to antidepressants. While several classes of antidepressants have been developed for the treatment of depression, over one-third of patients do not respond to conventional antidepressants, and all currently available antidepressants require weeks of continuous administration to achieve therapeutic effects. The delay in the onset of therapeutic effects from the time of taking antidepressants can put patients at risk for suicide. Therefore, there is a need in the literature to develop and identify novel antidepressants that do not work on conventional targets and that have fast-acting properties.
The primary goals of this dissertation were to investigate the pattern of cognitive impairments following CORT treatment and to examine the antidepressant potential of TNF-α receptor inhibition and reelin. To begin, in Chapter 2, I examined the effect of repeated CORT injections on depression-like behaviour using the forced swim test, the object-location, object-in-place, and object-recognition memory tests, and sensorimotor gating using prepulse inhibition. These data suggested that CORT increases depression-like behaviour while simultaneously impairing hippocampal and prefrontal cortex-dependent memory and sensorimotor gating. In Chapter 3, I examined the effects of the TNF-α inhibitor etanercept on CORT induced depression-like behaviour, cognition, and markers of synaptic plasticity through post-mortem analysis of brain tissue. I found that CORT increased depression-like behaviour on the forced swim test and impaired object memory. CORT also impaired several post-mortem markers of hippocampal plasticity, and etanercept restored these measures back to control levels.
In Chapter 4 I examined the antidepressant potential of intrahippocampal reelin infusions and its effects on cognition and markers of synaptic plasticity. I found CORT treatment increased depression-like behaviour on the forced swim test and impaired object memory. Reelin treatment restored both of these measures back to control levels within one day. CORT also decreased markers of hippocampal plasticity, and reelin restored these measures back to control levels. Finally, in Chapter 5, I examined the contribution of AMPA signaling to the antidepressant effects of reelin. I found that infusion of the AMPA antagonist CNQX blocked reelin’s antidepressant effects on the forced swim test, without altering CORT’s pattern of changes on markers of hippocampal plasticity. The results of this dissertation reveal novel compounds with antidepressant properties that warrant further investigation into their potential use in humans